MYC, a potent proto-oncogene, is aberrantly and widely expressed in human cancers, including the leukemias and lymphomas. The long-term goal of this proposal is to discover the molecules that are necessary to sustain MYC-driven tumors, T-cell acute lymphoblastic leukemia (T-ALL) in particular, and hence might serve as useful targets for the development of novel molecular therapeutics. Using a transgenic zebrafish model in which murine Myc is expressed in thymocytes and reliably generates T-cell leukemia, I conducted a dominant genetic modifier screen to identify and study oncorequisite genes whose mutation delays the onset of leukemia. My screen pinpointed a specific gene encoding dihydrolipoamide Ssuccinyltransferase (DLST) whose heterozygous inactivation significantly delays the onset of lymphoma/leukemia in zebrafish expressing the Myc oncogene. Zebrafish Dlst was upregulated in tumor cells with Myc overexpression, compared to normal cells without Myc overexpression. In addition, this upreguiation of DLST was associated with an increased fraction of cells in 8 phase and genomic instability. Tumor cells with 50% reduction of Dlst tended to be in G1 phase and morphologically more differentiated with a stable genome. I have clarified the importance of the human ortholog of DLST in T-ALL and found that DLST is aberrantly upregulated in the majority of T-ALL cell lines. Small molecule treatment of both human T-ALL cell lines and zebrafish with lymphoma is effective, leading to less viable cells in vitro and delayed tumor progression in vivo. Hence, I consider the human ortholog of this Kreb's cycle transferase as a promising therapeutic target for treating human T-ALL. During ROO phase of the grant, I will further characterize the importance of DLST in human neuroblastoma pathophysiology (new Aim 1) and identify its synergic genes and pathways (new Aim 2). Meanwhile, I will identify additional oncorequisite genes in MYC-mediated transformation through zebrafish genetic screens (Aim 3). The rationale and feasibility of this approach are well-illustrated by my data acquired during the K99 phase.